2-Estradiol (EB) has neuroprotective effects in several neurodegenerative diseases. Additionally, EB protects against status epilepticus (SE)-induced neuronal damage in the hilus of the hippocampal dentate gyrus. This protection occurs only in female but not in male rats. Preliminary studies have shown that neuroprotection is associated with increased late phase inhibition in the dentate gyrus determined by paired pulse stimulation. As this finding suggests participation of slow, G-protein linked neurotransmitter systems, metabotropic glutamate receptors (mGluR) and neuropeptide Y (NPY) were investigated. Both NPY and mGlu receptors seem to be involved and complement each other. As dentate gyrus filters the activity coming from the entorhinal cortex, neuroprotective effects of EB on hilar neurons may be associated with enhanced filtering features. Main hypothesis of this proposal is that in females, EB increases inhibition in the dentate gyrus. The increase in the denatate gyrus inhibition is mediated by the NPY and mGluR systems and results in enhanced filtering of incoming seizure activity to the hippocampus leading thus to neuroprotective effects on hilar neurons. Specific aims are to determine: Whether 1A. EB increases dentate gyrus inhibition. 1B. EB-induced increase in inhibition involves NPY and mGlu receptors. 1C. EB affects both feed-forward and feed-back inhibition, 1D. EB induces changes in NPY and mGluR expression. 2A. EB prevents spread of epileptiform activity through the dentate gyrus via activation of NPY and mGlu receptors. 2B. EB changes glutamate release at the inputs of dentate granule cells and their intrinsic properties. 3. The effects of blockade of NPY and mGlu receptors on EB-induced neuroprotection against SE-induced hilar damage. Groups include gonadectomized female rats treated with EB, progesterone, EB+progesterone or oil, and also gonadally intact female rats treated with EB or oil. Methods include in vitro studies in combined entorhinal cortex-hippocampus slices, paired pulse stimulation, use of specific NPY and mGluR antagonists, intracellular recordings, immunohistochemistry, histology, stereological cell counting, in vivo induction of SE as well as blockade of NPY and mGlu receptors. Here, novel mechanisms of EB action in the hippocampus involving NPY and mGluR interactions are proposed. The findings from our studies will also bring insights into understanding of gender-specific expression of such processes as depression/anxiety, stress processing, memory, and cognition.2-Estradiol has neuroprotective effects in several neurodegenerative diseases including the seizure-induced hippocampal damage. This proposal is focused on determining the mechanisms involved in 2-estradiol-induced neuroprotection in the hippocampus. We found that administration of 2-estradiol induces expression of neuropeptide Y, an inhibitory and neuroprotective peptide, in the dentate gyrus. This structure is an entry to the hippocampus proper and has filtering function. We will investigate how this increase of inhibitory neuropeptide will enhance the dentate gyrus filtering of incoming activity such as seizures and how this increased filtering can affect seizure-induced hippocampal damage.